title: Prior immunization with severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) nucleocapsid protein causes severe pneumonia in mice infected with SARS-CoV.
abstract: The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7-8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-gamma, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-beta), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.
authors.affiliation: Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yasui
authors.forename: Chieko
authors.initials: C
authors.lastname: Kai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kitabatake
authors.forename: Shingo
authors.initials: S
authors.lastname: Inoue
authors.forename: Misako
authors.initials: M
authors.lastname: Yoneda
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokochi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kase
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sekiguchi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Morita
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Hishima
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Katsuo
authors.initials: K
authors.lastname: Karamatsu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yasutomi
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Shida
authors.forename: Minoru
authors.initials: M
authors.lastname: Kidokoro
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Mizuno
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Michinori
authors.initials: M
authors.lastname: Kohara
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D002460:Cell Line; D002522:Chlorocebus aethiops; D000086462:Coronavirus Nucleocapsid Proteins; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D019590:Nucleocapsid Proteins / Q000008:administration & dosage / Q000276:immunology*; D011024:Pneumonia, Viral / Q000276:immunology* / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D012720:Severity of Illness Index; D014709:Vero Cells; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D000086462:Coronavirus Nucleocapsid Proteins; D016207:Cytokines; D019590:Nucleocapsid Proteins; D012333:RNA, Messenger; D014765:Viral Vaccines